title: Increased tumor uptake of chemotherapeutics and improved chemoresponse by novel non-anticoagulant low molecular weight heparin.
abstract: BACKGROUND
  Recent prospective clinical trials of low molecular weight heparins (LMWHs) have demonstrated that these agents may provide significant advantages in terms of progression-free and overall survival in certain subgroups of cancer patients. The mechanisms of improved survival associated with LMWHs are not known, and may involve direct and/or indirect effects on tumor growth. The purpose of this study was to investigate the effects of LMWH and a sulfated non-anticoagulant LMWH (S-NACH) on tumor chemotherapeutic uptake and chemoresponse.
  
  
  METHODS
  LMWH and S-NACH were tested for their ability to reduce tumor growth and tumor-associated angiogenesis using three different in vivo models. Biodistribution studies were undertaken to determine the effect of these agents on uptake of paclitaxel (PACL) and doxorubicin (Dox) by breast cancer tumor xenografts.
  
  
  RESULTS
  LMWH and S-NACH (10 mg/kg s.c. daily) effectively limited tumor growth of human A549 lung adenocarcinoma xenografts in the nude mouse. In an MDA453/LCC6 breast tumor xenograft model, PACL plus S-NACH showed significant (p < 0.01) tumor growth suppression and improved survival when compared to PACL alone. LMWH increased [(124-)I]-PACL uptake into MDA453/LCC6 tumors, with tumor:muscle ratios several fold greater than that of [(124-)I]-PACL alone 24 h post-injection. Similarly, LMWH and S-NACH significantly (p < 0.01) increased the uptake of Dox by 1.5-2 fold in MCF7 Dox-resistant tumor xenografts.
  
  
  CONCLUSIONS
  Protocols utilizing adjuvant or neo-adjuvant therapy with LMWH or S-NACH could lead to increased tumor chemo responsiveness, potentially overcoming tumor chemoresistance.
authors.affiliation: The Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Room 238, Rensselaer, NY 12144, USA. Patricia.Phillips@acphs.edu
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Phillips
authors.forename: Murat
authors.initials: M
authors.lastname: Yalcin
authors.forename: Huadong
authors.initials: H
authors.lastname: Cui
authors.forename: Hani
authors.initials: H
authors.lastname: Abdel-Nabi
authors.forename: Munawwar
authors.initials: M
authors.lastname: Sajjad
authors.forename: Ralph
authors.initials: R
authors.lastname: Bernacki
authors.forename: Jean
authors.initials: J
authors.lastname: Veith
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002642:Chick Embryo; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006801:Humans; D007457:Iodine Radioisotopes; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000925:Anticoagulants; D000972:Antineoplastic Agents, Phytogenic; D006495:Heparin, Low-Molecular-Weight; D007457:Iodine Radioisotopes; D004317:Doxorubicin; D017239:Paclitaxel